title: Thiazolidinone-peptide hybrids as dengue virus protease inhibitors with antiviral activity in cell culture.
abstract: The protease of dengue virus is a promising target for antiviral drug discovery. We here report a new generation of peptide-hybrid inhibitors of dengue protease that incorporate N-substituted 5-arylidenethiazolidinone heterocycles (rhodanines and thiazolidinediones) as N-terminal capping groups of the peptide moiety. The compounds were extensively characterized with respect to inhibition of various proteases, inhibition mechanisms, membrane permeability, antiviral activity, and cytotoxicity in cell culture. A sulfur/oxygen exchange in position 2 of the capping heterocycle (thiazolidinedione-capped vs rhodanine-capped peptide hybrids) has a significant effect on these properties and activities. The most promising in vitro affinities were observed for thiazolidinedione-based peptide hybrids containing hydrophobic groups with Ki values between 1.5 and 1.8 μM and competitive inhibition mechanisms. Rhodanine-capped peptide hybrids with hydrophobic substituents have, in correlation with their membrane permeability, a more pronounced antiviral activity in cell culture than the thiazolidinediones.
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University , Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Nitsche
authors.forename: Verena N
authors.initials: VN
authors.lastname: Schreier
authors.forename: Mira A M
authors.initials: MA
authors.lastname: Behnam
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018929:Cell Culture Techniques; D003716:Dengue Virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D010455:Peptides; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D053778:Thiazolidines; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases